A recent article from Paton et al. “Exposing Anopheles mosquitoes to antimalarials
blocks transmission of Plasmodium parasites”
1
has deservedly drawn considerable interest. In this landmark study, the authors showed
that adding atovaquone to a glass substrate on which blood-fed Anopheles mosquitoes
rested led to killing of Plasmodium falciparum parasites resident in the midgut blood
meal. The atovaquone concentrations required for effective killing were below those
of permethrin, a potent neurotoxic insecticide used in long-lasting insecticide-treated
bed-nets (LLINs). Modeling studies predicted that adding atovaquone to LLINs would
substantially increase bed-net effectiveness across a broad range of transmission
settings by reducing the prevalence of malarial infections. LLINs have been estimated
to account for 68% of the reduction in numbers of malaria cases since 2,000, but their
effectiveness is challenged by the rise of resistance to pyrethroid insecticides.
A vital need for new malaria-prevention strategies is underscored by evidence that
progress against malaria has plateaued in the past few years,
2
with an estimated 435,000 deaths in 2017.
Insecticides have traditionally been delivered to adult mosquitoes via aerosol contact,
ingestion of an “attractive toxic sugar bait,”
3
or surface contact on a bed-net or a wall. The idea of delivering an antimalarial
via surface contact with a mosquito seeking a blood meal is a truly innovative approach
to disrupting the Plasmodium transmission cycle, and has many attractions. First,
the technology and know-how to design and deliver compounds by this approach, optimized
through the use of LLINs, are well established. Second, Plasmodium parasite numbers
in the mosquito vector are low, with typically no more than five oocysts per midgut,
inside which form several thousand motile sporozoites that are infectious for humans.
By comparison, severely ill malaria patients can carry upward of 1012 asexual blood-stage
parasites. The mosquito stages, therefore, carry a far lower risk, than blood stages,
of generating resistance de novo (for atovaquone, P. falciparum resistance can be
selected from ∼108 asexual blood-stage parasites). Third, the potential impact of
transmission blocking, as elegantly demonstrated in the article, can be substantial
with the right compound and mode of action. Fourth, such an approach builds on and
complements other existing interventions, and could attack the parasite through mechanisms
not used in case management. These attributes would be unnecessary if bed-nets were
impregnated with fully effective insecticides that decimate local mosquito populations
and block transmission. Recent data, however, show that Anopheles resistance to pyrethroids
is spreading across Africa.
4,5
Despite the lower risk of de novo resistance selection targeting the numerical bottleneck
of Plasmodium development in the mosquito midgut, the net as a delivery system exposes
a sporontocidal drug to important risks. Contact exposure of mosquitoes may well be
much less than the studied 6 minutes, and drug exposure on a net surface is likely
to diminish over years of use. This would result in subinhibitory exposure, not unlike
adding chloroquine to salt in early malaria control efforts in Brazil.
6
Malaria control programs focus on minimizing the risk of treatment failure typically
through the use of fixed-dose combinations in which component drugs have distinct
resistance mechanisms.
7,8
As a matter of caution, a drug used to treat or prevent malaria, or, indeed, any drug
cross-resistant with such an agent, should ideally not be used in a transmission-blocking
strategy administered directly to mosquitoes, for example, on a bed-net or attractive
toxic sugar bait, as this strategy would risk losing the efficacy of essential life-saving
medicines. As stated in Paton et al.,
1
the use of atovaquone (a marketed antimalarial for both treatment and prophylaxis
in combination with proguanil) was a proof of principle, and was not presented as
a call to policy. Indeed, this novel approach to killing vector-stage parasites through
direct mosquito exposure will ideally use new transmission-blocking drugs with modes
of resistance that differ from those of approved products. The safest way to achieve
this would be with a drug that is effective against Plasmodium sexual stages in the
mosquito without exerting selective pressure on asexual blood-stage parasites. Several
antimalarial drugs with sporontocidal activity have been developed, including atovaquone
and, most recently, tafenoquine.
9,10
The pathway for approval of novel tools that prevent transmission, however, is arduous,
and particularly so for products that are solely measured by impact on an epidemiological
outcome.
11
The approach could be further challenged if an intervention that cured mosquitoes
of parasites was seen to improve mosquito fitness or fecundity.
12
Despite the challenges to developing bed-nets that deliver an anti-Plasmodium drug,
the good news is 3-fold. First, there is a renewed investment in developing and delivering
novel insecticides for nets and indoor residual spraying that effectively kill mosquitoes
resistant to current agents.
13
Second, new delivery systems, such as attractive toxic sugar baits, may allow more
standard dosing and greater compound stability compared with that with a complex net
matrix used over years.
14,15
Third, existing high-throughput phenotypic or target-based screens
16–18
could be adapted to identify sporontocidal antimalarials—compounds that would block
transmission in mosquitoes. Were such agents to have different mechanisms of resistance
from those of approved antimalarials and insecticides, then with careful optimization
of potency, physical properties, metabolic stability, and safety—all with a focus
on low cost—an appropriate mosquito-targeted transmission-blocking agent could be
delivered that is tailored for use within traditional vector control strategies. The
study by Paton et al.
1
stimulates a powerful new approach
19
to reducing the global burden of malaria and potentially other mosquito vector-borne
diseases.